Absorption

Most opioids are well absorbed via the subcutaneous (SQ) and intramuscular (IM) routes. Although GI absorption tends to be rapid, the oral bioavailability of many opioids is limited by extensive first-pass hepatic metabolism. After large oral (PO) doses, first-pass metabolism can become saturated, and oral bioavailability can be increased. Codeine and oxycodone are two opioids with very good oral bioavailability. The transdermal application of fentanyl is also used in clinical practice.

Distribution

Tissue uptake is variable and depends largely on the drug’s lipophilicity. Highly lipophilic compounds such as fentanyl readily penetrate the central nervous system (CNS), the dura of the spinal column, and tissue “reservoirs.” Opioids exhibit varying degrees of plasma protein binding and typically have large volumes of distribution. Serum concentrations of opioids should not be used as a gauge of clinical effect, because fat, skeletal muscle, lungs, and viscera act as reservoirs after opioid administration. Redistribution from saturated tissue depots can produce persistent or recurrent sedation after discontinuation of prolonged infusions of certain opioids such as fentanyl.⁴

Metabolism

Hepatic metabolism of opioids, typically by the P450 cytochromes, CYP3A4 and CYP2D6, can produce metabolites with either greater or lesser activity than the parent compound. For example, codeine is an active antitussive agent but an ineffective analgesic. The metabolism of codeine to morphine by CYP2D6 reduces its antitussive actions but markedly improves its analgesic properties. Morphine and its semisynthetic derivatives are converted to polar glucuronide metabolites, some of which are active. Metabolism of certain opioids also occurs by similar mechanisms in extrahepatic sites, especially the kidneys.

Elimination

Most opioids and their metabolites are cleared by the kidneys and require dosing adjustments in patients with renal failure. Biliary excretion is limited for most opioids.

Analgesia

Opioids are modulators of pain perception both at the level of the CNS and in the periphery. High concentrations of opioid receptors (largely of the mu subtype) are found in areas of the brain that are associated with analgesia. Cortical effects include decreased reception of painful sensory inputs and enhanced inhibitory outflow from the brain to the sensory nuclei of the spinal cord (dorsal root nuclei). In addition, there is decreased neurotransmission from peripheral afferent pain neurons to the spinal cord and from the spinothalamic tract to the brain. The net effect is decreased perception of nociceptive information. Analgesia is mediated by the mu, delta, and kappa opioid receptor subtypes (see Table 184-1). Morphine also appears to be an effective analgesic (via the mu opioid receptor) when administered intraarticularly.⁵ Tolerance develops to the analgesic effects with repeated use.

Very low doses of naloxone (e.g., 0.25 µg/kg/h) improve the efficacy of morphine analgesia, whereas at higher doses (1 µg/kg/h), analgesia is obliterated by naloxone. The mechanism of this effect is unclear.⁶

Euphoria

The euphoric effects of opioids are typically described as pleasant, floating sensations accompanied by a decrease in anxiety and distress. Not all exogenous opioids induce the same degree of euphoria. Activation of the mu/delta receptor complex in the ventral tegmental area, followed by dopamine release in the mesolimbic system, is most likely responsible for these effects.⁷

The degree of lipophilicity and CNS penetration is directly proportional to the euphoric properties of the opioid. For example, heroin, which enters the CNS with relative ease, is associated with greater euphoria than is the less lipophilic opioid, morphine.⁸ Fentanyl produces euphoric effects akin to those of heroin and is occasionally used as an adulterant in illicitly obtained heroin.⁹ The apparently enhanced euphoric effect of meperidine may be related to its lipophilicity and its ability to alter serotonergic neurotransmission.

By contrast, pentazocine, an agonist-antagonist opioid (i.e., an agent that is both an agonist at kappa receptors and an antagonist at mu opioid receptors), produces dysphoria and psychotomimesis (psychotic symptoms), an effect that most likely is mediated via kappa₂ receptor agonism.¹⁰ Pentazocine also can induce a withdrawal syndrome in opioid-tolerant individuals secondary to its mu opioid receptor antagonist effects. For these reasons, many patients previously exposed to pentazocine will cite allergies to it.

Sedation

Drowsiness and mental clouding are frequent in opioid-using patients. Different opioids are associated with different degrees of sedation despite equianalgesic dosing. Unlike sedative hypnotics, there is little or no associated amnesia unless the patient has been comatose. Electroencephalograms (EEGs) of opioid-sedated patients usually show slow delta waves that resemble sleep.

Respiratory Depression

All opioid agonists produce dose-dependent depression of ventilation. At equianalgesic doses, all opioid agonists lead to a similar degree of respiratory depression.^11,12 In the absence of secondary causes, death from opioid overdose is almost exclusively caused by respiratory depression.

Medullary mu₂ receptors are thought to be responsible for the development of respiratory depression. Stimulation of these receptors diminishes chemoreceptor sensitivity to hypercapnia, resulting in loss of hypercarbic ventilatory stimulation.¹³ Activation of these receptors also decreases the central response to hypoxia¹³ and inhibits the medullary and pontine respiratory centers that regulate the rhythm of breathing.¹² The combination of these effects leads to prolonged pauses between breaths, periodic breathing, hypopnea, bradypnea, and in extreme cases, apnea. It is important to note that the initial manifestation of respiratory depression may be a hypopnea, with or without a decrease in respiratory rate.¹²

Patients do not develop complete tolerance to the respiratory depressant effects of the opioids.¹⁴ For example, patients enrolled in methadone maintenance therapy can experience chronic hypoventilation and hypercapnia.¹⁵ A ceiling effect on respiratory depression exists with partial agonist and agonist-antagonist opioids such as nalbuphine and buprenorphine.

Certain groups of patients are particularly sensitive to the ventilatory depressant effects of opioids. These groups include the elderly, patients with chronically elevated PaCO₂ (e.g., some patients with chronic obstructive pulmonary disease [COPD]), and patients with a depressed level of consciousness for other reasons. A strong painful stimulus sometimes can transiently overcome or prevent respiratory depression. Similarly, during procedural sedation (e.g., for orthopedic reductions) when pain is relieved, respiratory depression can become apparent. Bronchoconstriction also can occur, most likely as a result of histamine release as well as indirect effects on bronchiolar smooth muscle. Depression of ventilation also can occur in patients receiving neuraxial opioid administration; these effects may be delayed and may be accompanied by respiratory depression (see “Neuraxial Opioids”).

Seizures

Seizures are rare with therapeutic use of most opioids, the primary exception being tramadol. If seizures occur in the setting of an acute opioid overdose, hypoxia is likely the cause. Seizures are associated with meperidine, propoxyphene, and tramadol toxicity. These drugs are further discussed in a later section. In a mouse model, naloxone antagonized the convulsant effects of propoxyphene, but not those of meperidine or its metabolite, normeperidine.¹⁶ Fentanyl-induced myoclonus can resemble seizure activity, but true seizures are rarely caused by fentanyl.¹⁷

Musculoskeletal Effects: Truncal Rigidity and Movement Disorders

Intravenous (IV) administration of opioids has been associated with motor abnormalities ranging from increased tone to overt myoclonus and involving the chest wall and other truncal muscles. This complication is seen when large doses of highly lipophilic opioids such as fentanyl, sufentanil, remifentanil, or alfentanil are administered rapidly by the IV route.¹⁸ Whereas it was previously thought that opioid actions at the level of the spinal cord were responsible for this effect, it now appears that a central dopaminergic effect may be contributory. Both naloxone and neuromuscular blockade can overcome rigidity. Vocal cord spasm, although rare, can cause closure of the vocal cords, leading to difficult bag-valve-mask ventilation. As noted, myoclonic activity resembling seizure activity has been observed in patients after being rapidly infused with large doses of fentanyl.¹⁷ Serotonin syndrome, characterized by coarse tremors, increased muscular tone, myoclonus, agitation, and autonomic instability, has been associated with the use of both meperidine and dextromethorphan in combination with other serotonergic agents.

Cardiovascular Effects

The peripheral arterial and venous dilation caused by opioids appears to be mediated by both central depression of vasomotor centers and histamine release.¹⁹ Hypotension occurs more frequently in stressed individuals and in those with decreased intravascular volume. Histamine release occurs via non–immunoglobulin (Ig)E-mediated mast cell degranulation.²⁰ Different opioids produce different degrees of histamine release; for example, meperidine and morphine produce much greater release of histamine than fentanyl and sufentanil.²¹ The severity of histamine-mediated responses can be reduced by slowing the rate of infusion, and hypotension can be reduced by optimizing intravascular volume. Use of Trendelenburg position and saline infusion are appropriate initial interventions for opioid-associated hypotension.

Bradycardia is occasionally associated with opioid use and is most often secondary to decreased excitatory stimulation and hypoxia. Primary opioid-induced bradycardia is relatively rare and is thought to be related to increased vagal nerve activity. Morphine also can exert direct slowing effects on the sinoatrial and atrioventricular nodes.

Overall, there are no consistent effects of opioids on cardiac output or the electrocardiogram (ECG). Wide-complex dysrhythmias and impaired contractility are associated with propoxyphene overdose via sodium channel blockade (class Ia antidysrhythmic effect). Illicit opioid use sometimes is associated with cardiac effects secondary to adulterants or co-ingestants; examples are quinine and cocaine (“speedball”). Chronic high-dose methadone use is associated with prolongation of the QT interval.²²

Effects on Cerebral Circulation

There are minimal effects on cerebral circulation except in the setting of respiratory depression with hypoventilation and increased arterial partial pressure of carbon dioxide (PaCO₂). Increased PaCO₂ causes cerebral vasodilatation and increased cerebral blood flow, both of which can increase intracranial pressure. These effects are of importance for the treatment of head injuries or increased intracranial pressure from other causes. In the absence of hypoventilation, opioids actually decrease cerebral blood flow and possibly intracranial pressure.

Morphine

Morphine is the prototypical opiate. Its pharmacologic effects are primarily caused by binding to the mu opioid receptor and, to a much lesser extent, the delta and kappa opioid receptors. It is a potent analgesic with typical opioid side effects including sedation, respiratory depression, decreased GI motility, nausea and vomiting, histamine release, and miosis. Despite its efficacy, morphine has relatively poor penetration into the CNS, largely because of its low lipid solubility.

The principal pathway of morphine metabolism is via glucuronidation in the liver and kidneys. The active metabolite, morphine-6-glucuronide, is more potent than morphine and is largely excreted via the kidneys. Renal failure can lead to accumulation of this active metabolite, leading to unexpected toxic effects after even low doses.

Heroin